β-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors
β-catenin/TCF/Lef controls a differentiation-associated transcriptional program in renal epithelial progenitors
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DOI：
10.1242/dev.006544
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发表时间：
2007-09-01
期刊：
影响因子：
4.6
通讯作者：
Barasch, Jonathan
中科院分区：
文献类型：
--
作者：
Schmidt-Ott, Kai M.;Masckauchan, T. Nestor H.;Barasch, Jonathan
在胚胎肾脏中，后肾间充质中的祖细胞按一定的顺序分化为特化的肾上皮细胞，其特征是形成细胞聚集体，转化为极化的上皮细胞，并沿着近端-远端轴线分裂。这一序列在整个肾脏发育过程中被重复，以产生肾单位。在这里，我们利用大鼠后肾间充质分化的器官培养模型，以同步而不是重复的方式概括了体内上皮化的特征，从而确定了与上皮分化相关的整体转录程序。我们观察到β-连环蛋白/TCF/Lef依赖转录的多个假定靶点的激活与上皮分化相一致。我们在培养的外植体中发现，上皮祖细胞中β-连环蛋白信号的孤立激活以Tcf/Lef依赖的方式诱导与上皮化相关的一组转录子，包括Pax8、细胞周期蛋白D1(Ccnd1)和Emx2。这与上皮祖细胞的抗凋亡和增殖作用有关，而TCF/LEF依赖转录受损的细胞会逐渐从上皮祖细胞中消失。在体内，Tcf/Lef反应基因组成了分化肾上皮祖细胞的保守转录程序，含有β-连环素的转录复合体直接结合到它们的启动子区域。因此，β-连环蛋白/TCF/Lef介导的转录事件控制与分化相关的转录程序的子集，从而参与上皮谱系的维持、扩张和阶段进展。
In the embryonic kidney, progenitors in the metanephric mesenchyme differentiate into specialized renal epithelia in a defined sequence characterized by the formation of cellular aggregates, conversion into polarized epithelia and segmentation along a proximal-distal axis. This sequence is reiterated throughout renal development to generate nephrons. Here, we identify global transcriptional programs associated with epithelial differentiation utilizing an organ culture model of rat metanephric mesenchymal differentiation, which recapitulates the hallmarks of epithelialization in vivo in a synchronized rather than reiterative fashion. We observe activation of multiple putative targets of beta-catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation of beta-catenin signaling in epithelial progenitors induces, in a TCF/Lef-dependent manner, a subset of the transcripts associated with epithelialization, including Pax8, cyclin D1 (Ccnd1) and Emx2. This is associated with anti-apoptotic and proliferative effects in epithelial progenitors, whereas cells with impaired TCF/Lef-dependent transcription are progressively depleted from the epithelial lineage. In vivo, TCF/Lef-responsive genes comprise a conserved transcriptional program in differentiating renal epithelial progenitors and beta-catenin-containing transcriptional complexes directly bind to their promoter regions. Thus, beta-catenin/TCF/Lef-mediated transcriptional events control a subset of the differentiation-associated transcriptional program and thereby participate in maintenance, expansion and stage progression of the epithelial lineage.